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An open-label randomised cross-over study to evaluate the albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes


- candidate number28167
- NTR NumberNTR6839
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR9-nov-2017
- Secondary IDsNL63792.099.17 Toetsingonline
- Public TitleAn open-label randomised cross-over study to evaluate the albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes
- Scientific TitleAn open-label randomised cross-over study to evaluate the albuminuria lowering effect of dapagliflozin, exenatide and their combination in patients with type 2 diabetes
- ACRONYMDECADE
- hypothesis
- Healt Condition(s) or Problem(s) studiedAlbuminuria, Diabetes Mellitus Type 2 (DM type II)
- Inclusion criteria Type 2 diabetes
HbA1c ≥ 7.5% (58 mmol/mol) and <10% (86 mmol/mol)
eGFR > 30 ml/min/1.73m2
Albumin:creatinine ratio >3.5mg/mmol and ≤100 mg/mmol
Age ≥ 18 years
RAS-blockade either by ACEI or ARB, or willingness to start ACEI or ARB treatment
Written informed consent
- Exclusion criteria Pregnant women and women of child-bearing potential who are not using reliable contraception
Cardiovascular disease: myocardial infarction, angina pectoris, percutanous transluminal coronary angioplasty, coronary artery bypass grafting, stroke, heart failure (NYHA I-IV) < 6 months before inclusion
Uncontrolled blood pressure (office bp > 160/ 100 mmHg)
Active malignancy
History of autonomic dysfunction (e.g. history of fainting or clinically significant orthostatic hypotension)
Participation in any clinical investigation within 3 months prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.
Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing
History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.
Use of SGLT-2 inhibitor or GLP1-RA.
Lithium use
Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:
o Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
o Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
o Pancreatic injury or pancreatitis within the last six months;
o Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at inclusion visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt;
o Evidence of urinary obstruction of difficulty in voiding at screening
- mec approval receivedno
- multicenter trialno
- randomisedyes
- masking/blindingNone
- controlActive
- groupCrossover
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-mrt-2018
- planned closingdate1-mrt-2020
- Target number of participants17
- InterventionsDapagliflozine
Exenatide
- Primary outcomeAlbuminuria reduction
- Secondary outcome Correlation in albuminuria response with each intervention
Change from baseline in extracellular volume
Change from baseline in fractional lithium excretion
Correlation between change in albuminuria and extracellular volume
Change in blood pressure
Change in weight
Assessment of pharmacokinetic parameters of each intervention
- TimepointsTreatment periods last 6 weeks, with 9 weeks of wash-out in between consecutive treatment periods.
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIES H. Lambers Heerspink
- CONTACT for SCIENTIFIC QUERIES H. Lambers Heerspink
- Sponsor/Initiator University Medical Center Groningen (UMCG)
- Funding
(Source(s) of Monetary or Material Support)
Astra Zeneca
- Publications
- Brief summaryRationale: Albuminuria is present in about 30% of patients with type 2 diabetes and is associated with increased renal and cardiovascular risk. Drugs which decrease albuminuria have been shown to confer renal and cardiovascular protection. Glucagon-like peptide receptor agonists (GLP1-RA) and sodium-glucose co-transporter 2 (SGLT-2) inhibitors are the two latest new drug classes for the management of type 2 diabetes. These drugs lower HbA1c when given as monotherapy or as adjunct to other glucose lowering drugs. Interestingly, both drug classes show beneficial effects on multiple cardiovascular risk factors including albuminuria and they have been shown to reduce renal and cardiovascular risk. It is unknown whether the combination of both drug classes confers an even more beneficial effect than either treatment alone on albuminuria. In addition, the mechanism by which these drugs lower albuminuria is not completely understood but it is possible that the albuminuria lowering effect is in part explained by the natriuretic effects of these drugs.

Objective: The main objective of the study is to determine the albuminuria lowering effect of the GLP1-RA exenetide, SGLT-2 inhibitor dapagliflozin and their combination in patients with type 2 diabetes and micro- or macroalbuminuria. Secondary objectives are to assess the effect of dapagliflozin, exenatide and their combination on extracellular volume and fractional lithium excretion (as measure of tubular sodium reabsorption), to assess the effect of dapagliflozin, exenatide and their combination on blood pressure and body weight, to determine the correlation in albuminuria-lowering response of dapagliflozin and exenatide within each individual, and to evaluate the correlation between the pharmacokinetics of dapagliflozin and exenatide and their albuminuria lowering effect

Study design: A randomized, prospective, single centre, crossover trial with a total duration of 46-50 weeks.

Study population: Patients type 2 diabetes of at least 16 years or older and elevated albuminuria (3.5-100 mg/mmol) already receiving a stable (same dose at least 4 weeks) of an ACE-inhibitor or Angiotensin Receptor Blocker.

Intervention: Patients receive in random order 6 weeks of treatment with the GLP1-RA exenatide 2 mg/week s.c., 6 weeks of treatment with the SGLT-2 inhibitor dapagliflozin 10 mg/day and 6 weeks of treatment with the combination of exenatide and dapagliflozin, with 9-weeks wash-out periods in between.

Main study parameters/endpoints: The main study endpoint is the change in albuminuria from baseline at the end of each treatment period.
- Main changes (audit trail)
- RECORD9-nov-2017 - 10-dec-2017


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